Follistatin Gene Therapy for

sIBM and Becker Muscular Dystrophy

Jerry R Mendell, MD Research Institute at Nationwide Children’s

Hospital

The Clinical Problem •  Quadriceps muscle weakness

–  Becker muscular dystrophy –  Inclusion body myositis

•  Frequent falls –  Limb fractures –  Loss of ambulation

•  Improving quadriceps muscle strength would result in a

“clinically meaningful outcome”

Resistant to Approaches

•  Weight training

•  Electrical Stimulation

•  Anabolic Steroids

Myostatin Circulates Propeptide Complex Activated

Protease Cleavage

Activin Receptor

M M

M M

MYOSTATIN REGULATION OF MUSCLE SIZE

INHIBIT BINDING Gene mutation

Antibody Peptides

Myostatin Regulates Muscle Growth

Myostatin Gene Mutation

• Targeted disruption of the myostatin gene: increases muscle size and body weight

- “Mighty” Mouse (Mstn KO) - Double-muscled cow (Mstn Het)

- Newborn with gene mutation mutation N Engl J Med. 2004;350:2682-8

McPherron et al 1997

Wyeth sponsored 11 Center Trial (10 USA;1GB) Using antibody to myostatin

•  No Clinical benefit •  High dose cohorts developed skin hypersensitivity reactions

Ann Neurology March 11, 2008

Circulating complex Propeptide-myostatin M M

Propeptide cleavage

M M

FOLLISTATIN

Activin Receptor

AAV-FOLLISTATIN

Follistatin Gene Therapy

INJECT AAV INTO MUSCLE

Follistatin Gene 1 2 3 4 5 6a 6b

1 2 3 4 5 1 2 3 4 5 6b

1) Alternative Splicing

Pre-FS317 Pre-FS344 2) Translation

N Domain FS Domain I FS Domain II FS Domain III N Domain FS Domain I FS Domain II FS Domain III C

3) Cleavage of Signal Peptide (29aa)

FS 288 FS 315 Circulating isoform Tissue bound isoform

SP SP

N Domain FS Domain I FS Domain II FS Domain III N Domain FS Domain I FS Domain II FS Domain III C

Treatment of mdx with AAV1.FS344

Q and TA Bilateral

1e11

1e10

Tibialis Anterior

5 mo post gene transfer

> 1year>

CK

Hind

Limb

Grip S

tren

gth

3 months post gene transfer

Moving to Non-Human Primates to Simulate Clinical Trial

Can the Mouse Studies Predict Safety and Efficacy in a Clinical

Trial ?

FS344 Gene Transfer to Monkey

AAV1-FS

Control

5 MO POST GENE TRANSFER

Functional Improvement Promoter

Twitch Force Tetanic Force

Untreated Leg

FS-Treated

Untreated leg

FS-Treated

MCK 17.0 19.0 (11.8%) 65.0 73.0 (12.3%)

CMV 19.0 24.0 (26.3%) 64.0 72.0 (12.5%)

No Cardiotoxicity** 5 and 15 months

Study Training - 15March2012

Clinical Chemistries Monkeys used in Pre-clinical Studies

Necropsies of NHP used in Pre-Clinical Studies

•  Full necropsy on all monkeys –  slides on each organ evaluated by a board

certified veterinary pathologist blinded to treatment group (control vs FS)

•  No treatment-related abnormalities found in heart, liver, lung, spleen, kidney, testis, ovary and uterus (5 &15 months)

Taking this to Clinical Trial

Prepare for Clinical Trial Develop Outcome Measures

r = 0.578 p < 0.001

r=0.603 p < 0.001

AAV1.CMV.Follistatin IND

09-12-11

8 in

Final Step Before Clinical Trial Submit the IND

AAV1.Follistatin Clinical Trial

•  18 subjects (9 sIBM /9 Becker muscular dystrophy patients)

•  Dose escalation study injection of AAV1.CMV.FS344 into quadriceps

•  Outcome: 6MWT and Quantitative myometry of Knee extensors

•  Muscle biopsies at 3 months and 6 months •  Patients will be followed for 2 years

Circumventing Barriers to Negative Gene Therapy Trial

•  Avoid pre-existing immunity to AAV –  Some individuals have been exposed to virus

and should be excluded from the trial •  Avoid immune immune response to

follistatin –  Less likely but possible and patients should

be checked

Hopefully Making Progress For Challenging Conditions !

Three Patients have been treated to date and no adverse events encountered

SUCCESS IS A TEAM EFFORT ! Center at

Nationwide Children’s Hospital Cellular Immune Christopher Walker Katie Campbell Gene Therapy Center Brian Kaspar PRE-CLINCAL EFFORTS K Reed Clark VECTOR MANUFACTURING Chris Shilling PROGRAM MANAGER Xiomara Rosales FDA LIAISON